A new study has uncovered how antidepressants affect different groups of serotonin-producing brain cells in opposite ways, offering new insights into why selective serotonin reuptake inhibitors (SSRIs) can cause unpleasant side effects at the start of treatment but lead to symptom relief over time.

Antidepressants are among the most widely prescribed medications in the world. In Sweden, more than one in ten people currently use an antidepressant, and SSRIs are by far the most common type.

“Yet we still understand surprisingly little about what these drugs actually do in the brain. Our study set out to map the gene-expression changes SSRIs induce in their primary target, the brain's serotonin neurons”, says Iskra Pollak Dorocic, Assistant Professor at the Department of Biochemistry and Biophysics at Stockholm University.

The study focused on fluoxetine, one of the most widely prescribed SSRIs, examining its effects on the brain’s main serotonin-producing region, the Dorsal Raphe Nucleus. Using a cutting-edge technique called spatial transcriptomics[LE1.1], the research group mapped changes in gene activity after both short-term and long-term treatment.

“Rather than treating the serotonin system as a single uniform population, we used spatial transcriptomics to read out gene activity at high resolution and map different types of serotonin neurons in the same brain area. That allowed us to see that these neurons are far more diverse than a single label suggests, and importantly that they do not all respond to the drug in the same way”, says Iskra Pollak Dorocic.

The study revealed widespread changes in gene expression following SSRI treatment. Most notably, the researchers identified two distinct subpopulations of serotonin neurons that responded differently to the drug:

• One group showed increased expression of the neuropeptide prodynorphin (Pdyn) after short-term treatment. Pdyn signaling has previously been linked to stress-induced depressive symptoms in other parts of the brain. However, this effect diminished with longer exposure to the antidepressant. The research suggests that this temporary increase in Pdyn could be linked to the negative effects that some patients experience when first starting SSRI treatment, such as increased anxiety or worsening mood.
• A second serotonin neuron population responded in the opposite way. These cells instead expressed the neuropeptide thyrotropin-releasing hormone (TRH), and their activity increased only after prolonged treatment. TRH signaling has previously been linked to anti-depressive functions in other parts of the brain. The findings suggest that TRH may play a role in the therapeutic effects of SSRIs that typically emerge after several weeks of treatment.

The discovery highlights the complexity of the brain’s serotonin system and suggests that different serotonin neurons may contribute to different phases of antidepressant response.

“We found that two distinct serotonin neuron populations are pushed in opposite directions by the same drug, one early and transiently, and one slowly over weeks. That mirrors the clinical picture, where unpleasant effects often come first and relief comes later, and it gives us concrete molecular candidates to interrogate next”, says Iskra Pollak Dorocic.

The genes, pathways and cell types identified in the study provide valuable leads for future research into the biological mechanisms underlying depression. The findings could also help guide the development of more targeted antidepressant treatments with fewer side effects and improved effectiveness.